Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer

Abstract

Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxiaimmune classifier with potential application in patient prognostication and prediction of response to targeted therapy.Experimental Design: A 54-gene hypoxia-immune signature was constructed on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n ¼ 275) and validated using two independent cohorts (n ¼ 130 and 123). IHC was used to investigate the utility of a simplified protein signature. The spatial distribution of hypoxia and immune markers was examined using multiplex immunofluorescence staining.Results: Unsupervised hierarchical clustering of TCGA dataset (development cohort) identified three patient subgroups with distinct hypoxia-immune phenotypes and sur-vival profiles: hypoxia low /immune high , hypoxia high /immune low , and mixed, with 5-year overall survival (OS) rates of 71%, 51%, and 49%, respectively (P ¼ 0.0015). The prognostic relevance of the hypoxia-immune gene signature was replicated in two independent validation cohorts. Only PD-L1 and intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxia low / immune high and hypoxia high /immune low tumors were overrepresented in "inflamed" and "immune-desert" microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3 þ T cells (r ¼ À0.5464; P ¼ 0.0377), further corroborating the transcription-based classification.Conclusions: We developed and validated a hypoxiaimmune prognostic transcriptional classifier, which may have clinical application to guide the use of hypoxia modification and targeted immunotherapies for the treatment of HNC.

Stromal categorization in early oral tongue cancer

“…It shows a promising prognostic power in different epithelial cancers including the subsites of the head and neck [16,26]. Abundance of the stroma can form a barrier against the infiltration of immune cells and form an immune desert with only minimal infiltration of TILs usually associated with poor prognosis [35]. Immune cells constitute a major component of the tumor microenvironment [36].…”

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

“…A Birmingham research group developed a 54-gene hypoxiaimmune classifier to prognosticate patients with HNSCC, and uncovered that tumors that are high-hypoxia/low-immune are associated with "immune-desert" microenvironmental profiles (33). Hypoxia within a tumor microenvironment will increase the immune-inhibitory PD-L1 generation through the hypoxia-inducible factor (HIF)-1α signaling (33,34). An immune desert tumor microenvironment promotes immune evasion for cancer cells.…”

Identification and validation of a combined hypoxia and immune index for triple‐negative breast cancer

“…Hence, we further sought to validate the correlation of the CIHI and hypoxia. A previous study addressed the key hypoxia-related expression profiles in cancer [48]. We first compared the key hypoxia-related signatures in the high-risk and low-risk groups.…”